Abstract
Background64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1–4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone.ResultsWe found that the presence of pyridyl groups significantly increases 64Cu labeling conversion yield, with DOTA-2Py, −3Py and -4Py quantitatively complexing 64Cu at room temperature within 5 min (1 × 10− 4 M). [64Cu]Cu-DOTA-xPy (x = 2–4) exhibited good stability in human serum up to 24 h. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64Cu complexes. DOTA-xPy (x = 1–3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [64Cu]Cu-DOTA-xPy-αMSH retained good serum stability (> 96% in 24 h) and showed high binding affinity (Ki = 2.1–3.7 nM) towards the melanocortin 1 receptor.ConclusionDOTA-xPy (x = 1–3) are promising chelators for 64Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.
Highlights
64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition
We present the application of novel DOTA-pyridine derivatives and the labeling of a peptide targeting the Melanocortin 1 receptor (MC1R)
Infrared (IR) analysis showed the decrease of the stretching absorption at 1700 cm− 1 for C=O and 1200 cm− 1 for C-N (Spreckelmeyer et al 2017), indicating that both COO and pyridyl moieties bind to the metal
Summary
One key assumption is that the imaging tracer has identical biodistribution as the therapeutic radiopharmaceutical. This assumption is not always true considering differences in molar activity (activity per mole of compound), in vivo stability and inherent biological sensitivity to even the slightest perturbations in pharmaceutical structure (Di 2015). While the unique decay profile permits 64Cu, in principle, to be a dual PET-imaging and targeted therapy isotope, the high positron branching ratio precludes the clinical use of 64Cu for radiotherapy. The pure β− emitter, 67Cu (t1/2 = 61.8 h) is available by high gamma irradiation and shows promise as an elementmatched theranostic pair for 64Cu PET imaging and 67Cu targeted therapy (Smith et al 2012). As one of the only copper isotopes that can be produced via proton irradiation on lower energy medical cyclotrons, 64Cu is more readily available over other isotopes, making it more ideal for use in imaging (McCarthy et al 1997)
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